Endogenous opioid peptides are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression (see G. T. Shearman et al. J. Pharmacol. Exp. Ther., 243, 591-597, 1987).
The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated.
The selectivities of the prototypical delta (naltrindole, U.S. Pat. No. 4,816,586) and kappa (norbinaltorphimine, nor-BNI, U.S. Pat. No. 4,649,200) opioid antagonists have been attributed to the presence of non-peptide “address mimics” which bear a functional relationship to key motifs in the putative delta and kappa addresses of the endogenous opioid peptides, dynorphin-A and enkephalin, respectively. P. S. Portoghese et al. J. Med. Chem. 1993, 36, 179-180 and U.S. Pat. No. 5,457,208 reported a series of NTI analogues in which the C5′ position of the indolic benzenoid ring is substituted with an alkyl amidine pendant.
U.S. Pat. No. 6,500,824 discusses a series of compounds that are reported to have activity as kappa antagonists and to be useful for treating conditions wherein antagonism of kappa receptors is indicated. One specific compound prepared therein is the compound 5′-guanidinyl-17-cyclopropylmethyl-6,7-didehydro-4,5-α-epoxy-3,14-dihydroxyindolo[2′,3′:6,7]-morphinan ditrifluoroacetate dehydrate (Example 1 therein):
Currently, the corresponding bis-hydrochloride salt (GNTI bis-hydrochloride) is under development for the treatment of type-2 diabetes. In spite of this, there is currently a need for compounds and compositions that are more efficacious and/or that have greater stability than the GNTI bis-hydrochloride salt.
Lipoic acid (LA) has been reported to lower glucose in experimental animals. Additionally, there is limited clinical data showing that LA can improve glucose utilization in individuals with type 2 diabetes. A clinical trial in 13 patients with type 2 diabetes found that a single intravenous infusion of LA improved insulin-stimulated glucose disposal by 50% compared to a placebo infusion (Jacob S, Henriksen et al., Arzneimittelforschung, 1995, 45(8), 872-874). In an uncontrolled pilot study of 20 patients with type 2 diabetes, intravenous infusion of LA for ten days also improved insulin sensitivity when measured 24 hours after the last infusion (Jacob S, Henriksen et al., Exp Clin Endocrinol Diabetes, 1996, 104(3), 284-288). A placebo-controlled study of 72 patients with type 2 diabetes found that oral administration of LA improved insulin sensitivity by 25% after four weeks of treatment (Jacob S, Rett et al., Biofactors, 1999, 10(2-3), 169-174; and Ziegler D. Treat Endocrinol, 2004, 3(3), 173-189).